Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism

Ben-Reuven, Lihi; Reiner, Orly

doi:10.1038/s41380-019-0594-y

Cited by 20 publications

(61 citation statements)

References 57 publications

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“…Proper cortical development and expansion are dependent on coordinated regulation of NPC proliferation and cell fate specification; accumulating evidence indicates that these processes are disrupted following MIA. For example, MIA enhances expression of cell cycle-related genes and alters NPC proliferation patterns, resulting in increased cortical thickness and neuron density, brain overgrowth, regions of cortical dysplasia, and layering defects (32,(48)(49)(50). In this context, our findings of increased cortical thickness and enhanced NPC proliferation in fetuses 1-week following MIA support previous findings and suggest endogenous dysregulation of NPC self-renewal and differentiation.…”

Section: Discussionsupporting

confidence: 89%

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

et al. 2020

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Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. A spectrum of behavioral abnormalities can be recapitulated in rodents by inducing MIA using the viral mimetic, PolyI:C. Many studies have focused on long-term changes in brain structure and behavioral outcomes in offspring following maternal PolyI:C exposure, but acute changes in prenatal development are not well-characterized. Using RNA-Sequencing, we profiled acute transcriptomic changes in rat conceptuses (decidua along with nascent embryo and placenta) after maternal PolyI:C exposure during early gestation, which enabled us to capture gene expression changes provoked by MIA inclusive to the embryonic milieu. We identified a robust increase in expression of genes related to antiviral inflammation following maternal PolyI:C exposure, and a corresponding decrease in transcripts associated with nervous system development. At mid-gestation, regions of the developing cortex were thicker in fetuses prenatally challenged with PolyI:C, with females displaying a thicker ventricular zone and males a thicker cortical mantle. Along these lines, neural precursor cells (NPCs) isolated from fetal brains prenatally challenged with PolyI:C exhibited a higher rate of self-renewal. Expression of Notch1 and the Notch ligand, delta-like ligand 1, which are both highly implicated in maintenance of NPCs and nervous system development, was increased following PolyI:C exposure. These results suggest that MIA elicits rapid gene expression changes within the conceptus, including repression of neurodevelopmental pathways, resulting in profound alterations in fetal brain development.

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Section: Discussionsupporting

confidence: 89%

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

et al. 2020

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“…Similarly, the reconstruction of the deep-layer neuron differentiation trajectory from our scRNAseq dataset revealed a higher proportion of progenitor cell populations compared to neuronal cell populations upon Hyper-IL-6 exposure (Figure 4). These results partially recapitulate the results from a mouse model of MIA where poly(I:C) treatment resulted in higher numbers and proliferative capacity of PAX6-positive vRGs (18). In the mouse, however, MIA also led to an overproduction of deep layer neurons (18).…”

Section: Discussionsupporting

confidence: 84%

“…Our findings suggest that Hyper-IL-6 treatment is mostly targeting RGs within DFOs. Previous studies have indicated that MIA in mice alters the proportions of proliferative versus neurogenic cell divisions at E12.5 culminating in an overproduction of deep-layer neurons later in development (18). To evaluate potential disturbances in the cell fate decisions of RGs upon exposure to Hyper-IL-6, we performed a series of immunohistochemical analyses to assess organoid morphology and the cell type compositional changes (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

“…Epidemiological studies, as well as animal and 2D in vitro models of MIA, have revealed possible molecular mediators of MIA, including IL-6, IL-17α, TNF-α, and IFN-γ, that drive the adverse neurodevelopmental outcomes (11, 16, 17, 22, 72). Among those, there is strong evidence for IL-6 playing a key role (11, 18). In our model, we therefore chose to focus on IL-6 signaling.…”

Section: Discussionmentioning

confidence: 99%

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Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

Sarieva

Kagermeier

Khakipoor

et al. 2022

Preprint

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Maternal immune activation (MIA) during the critical windows of gestation is correlated with long-term neurodevelopmental deficits in the offspring, including increased risks for autism spectrum disorder (ASD) in humans. Interleukin 6 (IL-6) derived from the gestational parent is one of the major molecular mediators, by which MIA alters the developing brain. In this study, we established a human three-dimensional (3D) in vitro model of MIA by treating induced pluripotent stem cell-derived dorsal forebrain organoids with a constitutively active form of IL-6, Hyper-IL-6. We validated our model by showing that dorsal forebrain organoids express the molecular machinery necessary for responding to Hyper-IL-6 and activate STAT signaling upon Hyper-IL-6 treatment. RNA sequencing analysis revealed the upregulation of major histocompatibility complex class I (MHCI) genes, which have been implicated with ASD. Immunohistochemical analysis as well as single-cell RNA-sequencing revealed a small increase in the proportion of radial glia cells. Single-cell transcriptomic analysis revealed the highest number of differentially expressed genes in radial glia cells with downregulation of genes related to protein translation in line with data from mouse models of MIA. Additionally, we identified differentially expressed genes not found in mouse models of MIA which might drive species-specific responses to MIA. Together, we establish a human 3D model of MIA, which can be used to study the cellular and molecular mechanisms underlying the increased risk for developing disorders such as ASD.

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“…Maternal immune activation (MIA) is associated with the onset of disorders such as ASD and schizophrenia (Fontes‐Dutra et al, 2020). MIA induction by poly(I:C) exposure enhanced PAX6 (paired box 6) expression in mice embryos resulting in cell cycle impairments and increased number of cortical neurons expressing COUP‐TF interacting protein 2 (CTIP2) in deeper layers (V and VI) (Ben‐Reuven & Reiner, 2019). In a complementary finding, in vitro exposure of neuronal progenitors to high doses of IL‐6 (mimicking MIA) increased STAT3 (signal transducer and activator of transcription 3) phosphorylation and reduced the differentiation of neurons that express CTIP2 and TBR1 (T‐box brain transcription factor 1) (Zuiki et al, 2017).…”

Section: Environmental Factors and Tfs In Psychiatric Disordersmentioning

confidence: 99%

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Santos-Terra

Deckmann

Fontes-Dutra

et al. 2021

Intl J of Devlp Neuroscience

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Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)—a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis—represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood‐brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location‐dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome‐environment interactions.

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Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism

Cited by 20 publications

References 57 publications

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats

Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

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